title: Increased parasite surface antigen-2 expression in clinical isolates of Leishmania donovani augments antimony resistance.
abstract: Resistance to sodium antimony gluconate (SAG) is a major cause of therapeutic failure in a large proportion of visceral leishmaniasis (VL) cases. Determinants of SAG resistance have been widely studied; however, the mechanism operating in clinical isolates is poorly understood. In the present study, expression of parasite surface antigen-2 (PSA-2) gene was studied in clinical isolates of Leishmania donovani comprising of antimony resistant (n=10) and sensitive (n=4) parasites. The expression of PSA-2 gene was found to be consistently high in SAG resistant clinical isolates (≥1.5-fold) at both transcript and protein level. Further, over-expression of PSA-2 in L. donovani isolates (LdPSA-2(++)) resulted in conversion of SAG sensitive phenotype to resistant. The LdPSA-2(++) parasites showed significantly decreased susceptibility towards SAG (>12-fold), amphotericin B (>4-fold) and miltefosine (>2.5-fold). Marked decrease in antimony accumulation and enhanced tolerance towards complement mediated lysis was evident in LdPSA-2(++) parasites. The study established the role of PSA-2 gene in SAG resistance and its potential as a biomarker to distinguish resistant and sensitive clinical isolates of L. donovani.
authors.affiliation: National Institute of Pathology, Indian Council of Medical Research, Safdarjung Hospital Campus, New Delhi, India.
authors.forename: Vasundhra
authors.initials: V
authors.lastname: Bhandari
authors.forename: Dhiraj
authors.initials: D
authors.lastname: Kumar
authors.forename: Sandeep
authors.initials: S
authors.lastname: Verma
authors.forename: Gurumurthy
authors.initials: G
authors.lastname: Srividya
authors.forename: Narendra Singh
authors.initials: NS
authors.lastname: Negi
authors.forename: Ruchi
authors.initials: R
authors.lastname: Singh
authors.forename: Poonam
authors.initials: P
authors.lastname: Salotra
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology; D000953:Antigens, Protozoan / Q000235:genetics*; D000954:Antigens, Surface / Q000235:genetics*; D000967:Antimony Sodium Gluconate / Q000494:pharmacology* / Q000627:therapeutic use; D004351:Drug Resistance / Q000235:genetics*; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000469:parasitology*; D015800:Protozoan Proteins / Q000235:genetics*; D014344:Trypanocidal Agents / Q000494:pharmacology*
chemical_list: D000953:Antigens, Protozoan; D000954:Antigens, Surface; D015800:Protozoan Proteins; D014344:Trypanocidal Agents; C072094:surface antigen P2, Leishmania; D000666:Amphotericin B; D000967:Antimony Sodium Gluconate
keywords: Antimony; Biomarker; Drug resistance; Leishmania donovani; PSA-2; Visceral leishmaniasis